Biology subjects

Amoroso, C.

Publications and source records attributed to Amoroso, C..

4 recordsLinked to original sources

bioRxiv2024

Estrogen-related differences in antitumor immunity and the gut microbiome contribute to sexual dimorphism of colorectal cancer

Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a pivotal role in the initiation and progression of CRC, and shapes anti-tumor immune responses but how the responsiveness of the immune system to the intestinal microbiota may contribute to the sexual dimorphism of CRC is largely unknown. Here, we studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n=184 male and female CRC patients and functionally tested the immune system-microbiome interactions in in vivo and in vitro models of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating iNKT cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of {beta}-glucuronidase activity are distinctive traits characterizing the gut microbiome of women affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. These results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer.

immunology↗

bioRxiv2023

Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion.

immunology↗

bioRxiv2022

Tumor infiltrating iNKT cells sustain neutrophil pro-tumorigenic functions influencing disease progression in human colorectal cancer

iNKT cells account for a relevant fraction of effector T-cells in the intestine. Although iNKT cells are cytotoxic lymphocytes, their role in colorectal cancer (CRC) remains controversial. From the analysis of colonic LPMCs of human and murine CRC specimens we report that tumor-infiltrating iNKT cells are characterized by an IL17/GM-CSF pro-tumorigenic phenotype, while maintaining cytotoxic properties in the adjacent non-tumoral tissue. Exposure of iNKT cells to the tumor-associated pathobiont Fusobacterium nucleatum blunted their cytotoxic capability and enhanced iNKT cell-mediated neutrophils chemotaxis, which upregulated PMN-MDSC gene signatures and functions. Importantly, in vivo stimulation of iNKT cells with GalCer restored their anti-tumorigenic functions. Survival analyses demonstrated that human CRC co-infiltration by iNKT cells and tumor-associated neutrophils correlates with negative outcomes. Our results reveal a functional plasticity of human intestinal iNKT cells with pro- and anti-tumorigenic activities in CRC, suggesting an iNKT pivotal role in shaping the cancer developmental trajectory.

immunology↗

bioRxiv2017

Catching up to a fast-moving target: Evaluation of a health system strengthening intervention in rural Rwanda 2005-2010 using data from repeated cross-sectional surveys

IntroductionAlthough Rwandas health system underwent major reforms and improvements after the 1994 Genocide, the health system and population health in the southeast lagged behind other areas. In 2005 Partners In Health and the Rwandan Ministry of Health began a health system strengthening intervention in this region.\n\nMethodsCombining results from the 2005 and 2010 Demographic and Health Surveys with those from a supplemental 2010 survey, we compared changes in health system output indicators and population health outcomes between 2005 and 2010 as reported by 21,338 women living in the intervention area and similar rural areas, controlling for potential confounding by economic and demographic variables.\n\nResultsOverall health system coverage improved similarly in both regions between 2005 and 2010, with an indicator of composite coverage of child health interventions increasing from 57.9% to 75.0% in the intervention area and from 58.7% to 73.8% in other rural areas. Despite experiencing poorer health outcomes in 2005, the intervention area caught up to or exceeded other rural areas on 23 of 25 indicators. Most notably, under-five mortality declined by an annual rate of 12.8% in the intervention area, from 229.8 to 83.2 deaths per 1000 live births, and by 8.9% in other rural areas, from 157.7 to 75.8 deaths per 1000 live births. Improvements were most dramatic among the poorest households.\n\nConclusionWe observed dramatic improvements in population health outcomes including under-five mortality between 2005 and 2010 in rural Rwanda generally, and in the intervention area specifically.\n\nSUMMARY BOXO_ST_ABSWhat is already known about this topic?C_ST_ABSO_LIMuch of the evidence that health system strengthening in rural Africa has improved health outcomes comes from studies of targeted regional interventions such as performance based financing or community health worker programs, rather than integrated interventions that encompass multiple components including infrastructure and supply chain investments, health management information system, workforce training and incentives at all levels, community health workers, and free services for poor patients.\nC_LIO_LIIn addition to these experimental or quasi-experimental studies, a series of case studies have documented individual nations, pathways to achieving millennium development goal 4 target, the reduction of under-five mortality by two thirds between 1990 and 2015.\nC_LIO_LIThese reports suggest that improvements in coverage of reproductive, maternal and child health indicators explain some, but not all, of the decline in child mortality and that these successes occurred in the context of national gains in health, nutrition and food security, sanitation, poverty reduction, and access to clean water.\nC_LI\n\nWhat are the new findings?O_LICoverage of most maternal and child health care interventions improved at a similar pace in our rural intervention area and other rural areas.\nC_LIO_LIDespite experiencing poorer health outcomes in 2005, our rural intervention area caught up to or exceeded other rural areas on 23 of 25 population health indicators by 2010.\nC_LIO_LIInfant and under-5 mortality declined in our rural intervention area even more precipitously than in other rural areas of Rwanda between 2005 and 2010.\nC_LI\n\nHow might this influence practice?O_LIThe process of strengthening national health systems often involves trade-offs between a focus on first testing individual programs that distributed widely, as is often practiced by pilot programs with multilateral institutions, or implementing multiple simultaneous programs locally. Our results show that integrated health system strengthening interventions can be locally adapted to enable the rapid expansion of health care coverage as well as dramatic improvements in population health outcomes.\nC_LIO_LIIntegrated multi-level interventions can also help narrow the health care coverage and outcome gap between richer and poorer members of a society.\nC_LIO_LINational governments can leverage nongovernmental partners to achieve the health related sustainable development goals through joint implementation of national health policy.\nC_LI

epidemiology↗